New Strategies in Non Small Cell Lung Cancer: Improving ... · CCR New Strategies New Strategies in Non–Small Cell Lung Cancer: Improving Outcomes in Chemoradiotherapy for Locally

CCR New Strategies

New Strategies in Non–Small Cell Lung Cancer: Improving Outcomesin Chemoradiotherapy for Locally Advanced Disease

Ramesh Rengan1, Amit M. Maity1, James P. Stevenson2, and Stephen M. Hahn1

AbstractThe past decade has seen significant breakthroughs in our knowledge of the tumor biology of non–small

cell lung cancer (NSCLC). Signaling pathways that are vital for tumor growth have been identified and have

been effectively targeted for pharmacologic intervention. Furthermore, advances in imaging and treatment

delivery have allowed radiation oncologists to deliver therapy more precisely to mobile tumors, while

minimizing the dose to surrounding critical structures. This article summarizes the implications of these

advances for the patient with unresectable locally advanced NSCLC and highlights ongoing work to

improve clinical outcomes in this disease. Clin Cancer Res; 17(13); 4192–9. �2011 AACR.

Background

Approximately 50,000 patients are diagnosed annuallyin the United States with stage III non–small cell lungcancer (NSCLC). These patients have locally advanceddisease, that is to say, not surgically resectable on the basisof extent of primary disease or regional nodal involvement.Specifically, their cancer has spread to lymph nodes in themediastinum either on the same side of the tumor (N2) oron the contralateral side (N3), or they have local invasionof vital structures, such as the trachea and esophagus,which cannot be resected (T4 tumors). In general, N2disease would place a patient into at least stage IIIA disease,whereas N3 disease would render them IIIB. Even withaggressive therapy, these patients have an extremely poorlong-term survival, on the order of 15 to 40%.

Current standard of care for locally advanced non–smallcell lung cancer. In the 1980s, the standard of care forinoperable locally advanced NSCLC was radiotherapy (RT)alone; however, this changed in the early 1990s with thepublication of a phase III trial done by the Cancer andLeukemia Group B (CALGB) group (1). This trial rando-mized patients with unresectable stage III and medicallyinoperable stage II NSCLC to RT alone, versus inductionchemotherapy followed by conventional RT, and showedan improvement in median survival from 9.6 months to13.7 months. This result was duplicated in a separate phaseIII trial run by the Radiation Therapy and Oncology Group(RTOG), which clearly established combined modality as

the standard of care in themanagement of locally advancedinoperable NSCLC (2).

The trials above used sequential chemotherapy followedby RT; however, the idea of combining the two concur-rently to take advantage of potential additive or synergisticchemosensitization has also been explored. In fact, 2 phaseIII randomized trials, one conducted by the West JapaneseLung Cancer Group (WJLCG; ref. 3) and another by RTOG,have shown an advantage to giving chemotherapy concur-rently with radiation versus the sequential approach, bothshowing an improvement inmedian survival from approxi-mately 13 months to 17 months (4). This improvement insurvival with the addition of concurrent chemotherapydoes come with a cost of increased esophageal toxicity.

In the past decade, an important technological improve-ment in the care of lung cancer patients has been theintroduction of 18F-fluorodeoxyglucose–positron emissiontomography computed tomography (18F-FDG-PET CT) as astandard component of the staging workup in patients withlung cancer. 18F-FDG-PET CT can often identify patientswith occult mediastinal nodal or distant metastatic diseasethat would otherwise go undetected on CT scans or bonescans alone (5, 6). One study analyzed findings in 73patients who had pathologically confirmed nodal diseaseidentified on either CT or 18F-FDG-PET and determinedthat the PET CT scan improved the accuracy of identifyingpathologically positive lymph node stations to 89% from75% with CT alone (7).

Opportunity for improving results. Despite improve-ment with combined modality therapy, both local controland survival still remain poor in locally advanced NSCLC.Le Chevalier found that the 1-year local control rate wasonly 15% for patients with unresectable NSCLC whoreceived 65Gy of radiation and chemotherapy (8). Improv-ing local control may lead to increased survival. The Con-tinuous Hyperfractionated Accelerated Radiotherapy(CHART) regimen without chemotherapy has been shownto improve both local control and survival when comparedwith standard dose RT (9, 10). In a European Organisation

Authors' Affiliations: 1Department of Radiation Oncology and 2Division ofHematology-Oncology, Department of Internal Medicine, University ofPennsylvania School of Medicine, Philadelphia, Pennsylvania

Corresponding Author: Ramesh Rengan, University of PennsylvaniaSchool of Medicine, Radiation Oncology, 2-Donner; HUP, 3400 SpruceStreet, Philadelphia, PA 19104. Phone: 215-662-2989; Fax: 215-349-5445; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-10-2760

�2011 American Association for Cancer Research.

ClinicalCancer

Research

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for Research and Treatment of Cancer (EORTC) study forlocally advanced NSCLC, the 2-year local control improvedfrom 19 to 31% with the addition of concurrent dailycisplatin to radiation, and the 2-year overall survivalincreased from 13 to 26% (11). Therefore, improvementin local control represents a principal goal in designing newstrategies to treat NSCLC.

On the Horizon

Exploiting tumor biologyNumerous signaling pathways are dysregulated in

NSCLC (Fig. 1). K-ras is mutated in 20 to 30% of NSCLC,the HER2/Erb-B2 receptor is overexpressed in up to 25% ofcases, and the epidermal growth factor receptor (EGFR) isoverexpressed in themajority of cases (12). Nanjundan andcolleagues did a proteomic screen and found that markersof the phosphoinositide 3-kinase (PI3K)/Akt and p38mitogen activated protein kinase (MAPK) pathway signal-ing pathways (e.g., p70S6K, S6, p38, and phospho p38), aswell as caveolin-1 and b-catenin, were differentiallyexpressed in lung cancer specimens compared with normallung tissue (13). A total of 4 to 6% of NSCLC contains achromosomal abnormality that produces a fusion genecomprising portions of the echinoderm microtubule-asso-ciated protein-like 4 (EML4) gene and the anaplastic lym-phoma kinase (ALK) gene (14). Patients with these

mutations may respond to an oral ALK inhibitor, becausetheir cancers may be driven by the EML4-ALK fusionprotein (15). Other driver mutations found in NSCLCinclude those in BRAF, PIK3CA, AKT1, MAP2K1, andMET (16). Agents have been developed for NSCLC thattarget the insulin-like growth factor 1 receptor (IGF-1R),histone deacetylation acetyltransferase (HDAC), and thehedgehog (Hh) signaling pathway (17). In this section, wefocus specifically on those approaches that have been triedto improve the radiation response, namely hypoxia modi-fiers, antiangiogenic agents, EGFR inhibitors, IGF-1 inhi-bitors, and PI3K/Akt inhibitors.

Hypoxia in non–small cell lung cancer. Hypoxia, whichexists in a variety of solid tumor types, including lung, headand neck cancer, breast cancer, and cancer of the cervix,may mediate tumor progression by activating genesinvolved in angiogenesis and metastasis (18–23). Com-pared with well-oxygenated cells, severely hypoxic tumorcells require 2 to 3 fold the dose of radiation to achieve thesame level of sterilization (24, 25). This requirement islikely due to the fact that most of the DNA damage inducedby radiation is indirect, mediated by the generation of freeradicals, which cannot occur in the absence of oxygen.Hypoxia also upregulates the expression of hypoxia-indu-cible factor-1 (HIF-1), a master transcription factor, andVEGF, a potent mediator of angiogenesis. Both VEGF andHIF-1 are potential targets for increasing the radiation

© 2011 American Association for Cancer Research

Ras

Raf

IGF-1EGF

EGFR

PIP2 PIP3PI3KIGF-1R

Gefitinib

NVP-BEZ235

Erlotinib

Cetuximab

Akt

p38MAPK Stat3ERK1/2

mTOR

Nelfinavir

P

PP P P

P

PP

Figure 1. Numerous signaling pathways are dysregulated in human cancers, including NSCLC. K-ras is mutated in 20 to 30% of NSCLC. EGFR isoverexpressed in the majority of NSCLC and mutated in a smaller subset. Other tyrosine kinase receptors that are overexpressed in NSCLC, although toa lesser extent, are IGF-1R and HER2/Erb-B2. Overexpression of these receptor kinases leads to activation of multiple downstream signaling pathways,including the extracellular signal regulated kinase 1/2 (Erk1/2) MAPK pathway, the p38 MAPK pathway, and the PI3K/Akt/mTOR pathway. Inhibitors areavailable that target various molecules in these pathways. Several EGFR inhibitors, including erlotinib, gefitinib, and cetuximab, and PI3K inhibitors, includingthe Novartis compound NVP-BEZ235, which also inhibits mTOR, have been used to radiosensitize NSCLC cells. The HIV protease inhibitor nelfinavir,which inhibits Akt phosphorylation, also radiosensitizes cells.

Chemoradiotherapy for Locally Advanced NSCLC

www.aacrjournals.org Clin Cancer Res; 17(13) July 1, 2011 4193




response in NSCLC. Zeng and colleagues showed thatwhen combined with radiation, the HIF-1 inhibitor TS-1retarded tumor regrowth of H441 NSCLC xenografts (26).In preclinical models, adding anti-VEGF therapy improvesthe therapeutic response to radiation (27). The compoundsYC-1 and PX-478 target HIF-1 and can increase tumorradioresponsiveness (28, 29). Williams and colleaguesshowed that the combination of radiation and cediranib(AZD2171), a highly potent inhibitor of VEGF receptors,cooperatively increased growth delay of Calu-6 NSCLCxenografts when given with radiation (30).

Targeting EGFR in non–small cell lung cancer. TheEGFR receptor (erb1/EGFR), a member of the family ofreceptor tyrosine kinases, is overexpressed in 80% ofNSCLC and mutated in a smaller percentage. EGFR activa-tion results in the activation of multiple intracellular sig-naling pathways, including the Ras and PI3K pathways.EGFR inhibitors, including the monoclonal antibodycetuximab, and the small molecule tyrosine kinase inhibi-tors gefitinib and erlotinib have been used in the clinic.

In preclinical models, EGFR inhibition can increaseradiosensitivity in NSCLC cell lines as reviewed previously(31). In mice bearing EGFR-expressing NSCLC xenografts,cetuximab and radiationmarkedly improved tumor growthinhibition over either agent alone (32). Similarly, Harari’sgroup showed that erlotinib and radiation act synergisti-cally to inhibit tumor regrowth of H226 NSCLC xenografts(33).

Targeting the IGF-1 pathway in lung cancer. The IGFaxis,which consists of IGF-1R, a rangeof stimulatory ligands(insulin, IGF-1, and IGF-2), and various IGF-binding pro-teins, has been implicated in the development and main-tenance of many cancers, including NSCLC (34). Agentsthat inhibit this pathway, including monoclonal antibo-dies, are available for clinical use (17). Targeted disruptionof IGF-1R has been shown to enhance the in vitro radio-sensitivity of some lung cancer cell lines (35). Therefore,there is some potential for using anti-IGF agents in combi-nation with radiation therapy for patients with NSCLC.

Targeting the PI3K pathway in lung cancer. Approxi-mately 50 to 83%ofNSCLC tumors exhibit activationof thePI3K pathway, which plays a key role in controlling cellproliferation, growth, and survival (36, 37). Activation ofthispathwayhasfurtherbeenassociatedwithradioresistanceinmany cell types (38).Gupta and colleagues showed that 3NSCLC cell lines with high P-Akt levels were radiosensitizedin vitro using the inhibitor LY294002 (36). A dual PI3K/mTOR inhibitor developed by Novartis, NVP BEZ-235, hasbeen shown to sensitizexenograftsofK-ras–mutatedNSCLCtumors to radiation (39). This agent is currently being testedin the clinic, but not in combination with radiation.

Our group and others have shown that the HIV proteaseinhibitor nelfinavir can interfere with PI3K-Akt signalingand radiosensitize a variety of tumor types includingNSCLC (40–42). We are currently testing nelfinavir in aphase I and II trial with concurrent chemoradiotherapy forlocally advanced NSCLC. The final results are still pending,but the initial clinical response data are promising (43).

The impact of the tumor microenvironment and relevancefor imaging. Despite elucidation of the intracellularmechanisms regulating radiation resistance, clinical trialstargeted at radiosensitization through inhibition of com-ponents of these pathways have yielded disappointingresults (44). One possible explanation for these poor out-comes is the inability to deliver adequate drug to the tumorbed, because of an extrinsic mechanism of tumor radiationresistance. One postulated mechanism of extrinsic radia-tion resistance in NSCLC is that abnormal tumor vascu-lature and increased interstitial fluid pressures lead toimpairment of tumor perfusion, resulting in inadequatedrug and oxygen delivery (45). Theoretically, targetedantiangiogenic therapy aimed at vascular normalization,through pruning of immature and abnormal blood vessels,could abrogate this mechanism of extrinsic radiation resis-tance through increased oxygen and drug delivery to thetumor (45). Indeed, it has been shown in preclinicalmodels that inhibition of VEGF signaling results in pruningof immature tumor vasculature and reduction of interstitialhypertension, thereby improving tumor hemodynamicsand oxygenation in animal models (46–48). An addedbenefit to vascular normalization would be to enhancethe delivery of chemotherapy to the tumor bed. Althoughprovocative, this theory has not yet been confirmed inpatients, and it is unclear what impact vascular normal-ization has on sensitivity to chemoradiotherapy in NSCLC.The hemodynamic characteristics of tumor microvascula-ture can be noninvasively assessed by dynamic contrast-enhanced CT (DCE-CT). DCE-CT has been shown to be auseful method for monitoring lung tumor vascularity (49–52), confirming the general value of tumor vascular assess-ment in this population.

Advances in concurrent chemoradiotherapy forlocally advanced non–small cell lung cancer

Functional imaging. The ability of RT to locally controlcancer is also dependent upon how well the tumor can bedelineated. 18F-FDG-PET scanning has helped greatly inthis regard; however, other novel tracers are also beingdeveloped. 18F-3-deoxy-3fluorothymidine (FLT), a markerthat images cellular proliferation, shows promise. Onestudy of 34 patients with NSCLC reported that 18F-FLT-PET showed better specificity, positive predictive value,and accuracy for N staging on a per-patient basis thandid 18F-FDG-PET (53). However, 18F-FDG-PET was foundto have higher sensitivity for identification of the primarytumor than 18F-FLT-PET.

As discussed above, tumor hypoxia is believed to be asignificant contributor to radiation resistance. Hence,there is a great deal of interest in imaging tumor hypoxia.18F-fluoromisonidazole (18F-FMISO), a radioactivelylabeled version of a well-studied nitroimidazole, wasone of the initial tracers to be developed for this purpose.However, the results in NSCLC have been mixed using thisisotope (54). A recent study reported poor correlationbetween 18F-FMISO uptake, 18F-FDG uptake, and tumormarkers of hypoxia and angiogenesis (55). However, other

Rengan et al.

Clin Cancer Res; 17(13) July 1, 2011 Clinical Cancer Research4194




markers of hypoxia have been developed that could havebroader applicability in NSCLC. The 2-nitroimidazole 18F-EF5 has also been used to image glioblastomas, but its usein NSCLC remains to be evaluated (56).Although biological imaging has proven valuable in

staging and improving the accuracy of tumor identificationfor target delineation, its role in assessing response totherapy still remains largely unexplored. In a recent pilotstudy from the University of Michigan, Kong and collea-gues found that 18F-FDG uptake during RT in NSCLCcorrelated with posttreatment scans, suggesting that tumormetabolic response during therapy may serve as an earlypredictor of outcome (57). Although intriguing, theseresults must be validated in larger studies in order to firmlyestablish the utility of 18F-FDG-PET scanning as a predictiveimaging biomarker for response to RT.Proton beam therapy. Particle beams, such as protons

and heavy ions, because of their physical properties, offerimproved dose distributions when compared with photonbeam radiation. Chang and coworkers reported that protonbeam RT significantly reduced dose to critical normal struc-tures, including the esophagus, spinal cord, and heart, evenwith dose escalation, when compared with photon therapyfor patients with early stage lung cancers (58). For locallyadvanced NSCLC in which the mediastinum is generallytreated, the criticalnormal structures include thespinal cord,heart, esophagus, and normal lungs. In order to meet doseconstraints for the spinal cord, the radiationoncologistmustuse oblique beams that avoid this structure, which results inradiation dose being spread to the surrounding normallungs. No prospective data to date have compared protonbeam RT to photons. However, a recently completed retro-spective comparative analysis of 678 NSCLC patients (pri-marily stage III) treated atMDAndersonCancer Centerwithproton beam RT to intensity-modulated radiation therapy(IMRT) photon or 3D-conformal RT revealed a significantdecrease in esophageal toxicitywith proton beamRT (59). Aprospective phase III randomized trial of IMRT photon (74Gy) versus proton beam RT [74 cobalt gray equivalents(CGE)] with concurrent chemotherapy for patients withunresectable locally advanced NSCLC is currently under-way. The results of this trial are eagerly anticipated.Accounting for tumor motion: image-guided radiotherapy

and 4-dimensional computed tomography–based treatmentplanning. In NSCLC, the radiation oncologist is facedwith the challenge of delivering radiation dose to a movingtarget embedded within an exquisitely radiosensitive,poorly functioning vital organ. Respiratory motion canresult in significant intrafraction variability in the locationof the gross tumor volume (GTV; refs. 60, 61). Stevens andcolleagues found that lung tumors move 5 to 10 mmduring quiet breathing, and often as much as 4.5 cm,and that movement cannot be predicted on the basis oftumor size, location, or pulmonary function (62). Oneapproach to account for this finding is to create a treatmentmargin around the GTV that accounts for the entirety oftumor excursion through the respiratory cycle. Modernmultislice spiral CT scanners permit a fourth dimension,

time, to be added to a 3-dimensional (3D) CT scan, whichcan image the tumor throughout the respiratory cycle. In a4-dimensional (4D) CT scan, images are captured during acomplete breathing cycle to allow for correlation of tumorlocation with respiratory motion. This approach allows theradiation oncologist to expand the treatment marginappropriately (63); however, this is achieved at a cost ofincreased toxicity to normal lung tissue because of thelarger treatment volume.

Several methods have been used to reduce intrafractionvariability during normal breathing. First, radiation can besynchronized to be delivered at specific points during thepatient’s respiratory cycle. The linear accelerator is turnedon and off accordingly while the patient breathes freely. Aninitial study by Mageras and colleagues found that tumormotion (as defined by average diaphragmatic excursion)was reduced from 1.4 cm to 0.3 cm with this technique,more commonly known as respiratory gating (64).

Although the respiratory-gating technique permits thepatient to breathe freely, active breathing control (ABC)relies on the patient’s voluntary control of breathing via theuse of an occlusive valve. This technique was originallydescribed by Wong and colleagues and has been used inNSCLC (65). Wilson and colleagues found that, with ABC,the tumor location showed no significant variation inposition over several weeks, the volume of normal lungirradiated was reduced by a median of 6.4%, and themedian spinal cord dose was reduced by a median of6.4% in 80% of the patients (66). A variation on theABC technique is the deep inspiration breath hold (DIBH)technique. Patients are simulated at deep inspiration andthen treated as such with port films for verification. Hanleyand colleagues found an intrabreath-hold reproducibilityof 1.0 (�0.9) mm and interbreath-hold reproducibility of2.5 (�1.6) mm, as determined from diaphragm position.They found that the volume of normal lung irradiatedcould be reduced on average by 30% with DIBH versus18% with respiratory gating (67).

With the advent of techniques such as respiratory gating,which allow the radiation oncologist to shrink the treat-ment volume, there is a critical need for accurate tumorlocalization on the treatment machine. Image-guided RT(IGRT) using cone beam CT (CBCT) technology nowpermits imaging and realignment of the patient at everytreatment to help reduce interfraction variability. Hugo andcolleagues found that a larger margin is required withgating or breath hold when CBCT-based IGRT is not usedthan when it is (9–10 mm versus 2–3 mm; ref. 68).

The 4D and IGRT techniques can be combined into 4Donline adaptive RT (ART) technique, in which inter- andintrafraction variability is accounted for, either on a dailybasis or after a given number of fractions (7). Harsoliaand colleagues did a comparative study examining 3D-conformal, 4D-union, 4D-offline adaptive with a singlecorrection (offline ART), and 4D-online adaptive withdaily correction (online ART) and found that 4D-ARTwith daily correction was optimal. This approach yieldeda decrease in treatment volumes (44% reduction), a






decrease in volume of normal lung irradiated (31%reduction), and reduction of mean lung dose (31%reduction; ref. 69). Although more labor intensive, 4D-ART with daily correction may allow radiation oncolo-gists to treat patients with extremely poor baseline lungfunction who otherwise could not have received defini-tive therapy for their disease.

Summary. Therehavebeen several recent advancementsin treatment planning, imaging, and delivery of therapeuticradiation in locally advanced NSCLC. The overall goal ofthese advances is the improvement of local control withoutan excessive increase in toxicity to the patient. As localcontrol improves, the importance of systemic sterilizationof disease is amplified.

Concurrent chemotherapyGiven the knowledge that distant relapse represents the

most common type of recurrence in patients with locallyadvanced NSCLC, the use of more efficacious systemictherapies in this setting should produce better outcomes.However, efforts to improve relapse-free and overall survi-val in these patients, through the incorporation of moderncytotoxic and/or targeted agents, have had minimal impacton clinical practice to date. Strategies have included apply-ing the agent of choice concurrently with RT or as con-solidation therapy after chemoradiation.

Concurrent use of the taxoids paclitaxel and docetaxel orthe vinca alkaloid vinorelbine with RT proved feasible, butshowedno gain in efficacywhen comparedwith the historicbenchmark results produced in studies of concurrent etopo-side and cisplatin (EP) agents that first appeared in the clinicapproximately 40 years ago (70–73). One caveat put forthwas the need to use the concurrent agent at full dose tomaximize systemic sterilization, but toxicity has limited theability to do so with the newer cytotoxics and was prohi-bitive in the instance of the antimetabolite gemcitabine(74). Consolidation full-dose docetaxel for 3 cycles follow-ing concurrent EP produced a promisingmedian survival of26 months in the Southwest Oncology Group (SWOG)9504 study (75). However, when this regimen was studiedby the Hoosier Oncology Group in a randomized trialversus concurrent EP alone, the docetaxel-containing armfailed to show an improvement in survival and significantlyincreased toxicity, including pneumonitis (76). The WestJapan Thoracic Oncology Group (WJTOG) recently pub-lished their phase III results indicating that full-dose con-solidation paclitaxel and carboplatin, following low-doseweekly paclitaxel-carboplatin concurrent with radiation,produced similar survival with significantly less toxicitythan WJTOG standard concurrent regimen of mitomycin-vindesine-cisplatin without consolidation (77).

The multitargeted antifolate pemetrexed has proven tobe one of the most active agents in nonsquamous NSCLCand shows radiosensitizing properties, as would beexpected with this drug class (78, 79). Phase I and II trialsreveal that pemetrexed can be safely administered at fulldose in combination with cisplatin and concurrent radia-tion in stage III NSCLC (80). The ongoing phase III

PROCLAIM trial will provide definitive data on concurrentand consolidation pemetrexed-cisplatin versus standardconcurrent EPwith consolidation platinum-based doubletsin locally advanced nonsquamous patients and may pro-duce a new standard of care if the primary endpoints aremet. Enrollment of 600 patients is planned.

Limited data with molecularly targeted agents are avail-able, the majority with EGFR inhibitors. The largest trial,SWOG 0023, was closed early when it was found that theaddition of maintenance daily gefitinib following EP-radia-tion and consolidation docetaxel produced inferior survi-val when compared with placebo following EP-radiationand docetaxel (23 versus 35 months, P ¼ 0.013; ref. 81).Concurrent strategies to take advantage of the radiosensi-tizing properties of EGFR-interactive agents may be moreattractive and have already become a standard approach inlocally advanced head and neck cancer (82). Blumenscheinand colleagues reported a median survival of 22.7 monthsand 50% 2-year survival in RTOG 0324, adding weeklycetuximab to low-dose weekly paclitaxel-carboplatin withRT, followed by consolidation cetuximab-paclitaxel-carbo-platin (83). On the basis of these results, the currentintergroup phase III trial (RTOG 0617) compares thisregimen to paclitaxel-carboplatin alone, as well as 2 dosesof RT, 60 versus 74 Gy. Erlotinib seems to be safe whengiven daily at full dose alone or in combination withchemotherapy, concurrent with full-dose thoracic radia-tion; however, efficacy data are lacking at present (84).Given the rapidly expanding knowledge of molecular pre-dictors of response to these agents in the metastatic diseasesetting, it can be expected that these markers will eventuallyprove useful in selecting stage III patients for the optimaluse of EGFR-targeted therapies with radiation.

Multiple trials of bevacizumab given concurrently andas maintenance with chemoradiation in small cell lungcancer and NSCLC were halted early because of enhancedtoxicity, chiefly in the form of tracheo-esophageal fistulaformation, leaving the future of this strategy in doubt(85). The Eastern Cooperative Oncology Group recentlylaunched a novel trial of maintenance bevacizumab plusthe MUC1 vaccine L-BLP25 following chemoradiation,with weekly paclitaxel-carboplatin and 2 cycles of con-solidation paclitaxel-carboplatin.

Conclusion

The past decade has seen significant advances in ourunderstandingof thebiologyofNSCLCand its role in tumorresistance to radiation. Additionally, we have significantlyimproved our ability to deliver radiation to the tumor whilesparing surrounding vital structures. It is through the cou-pling of these advances with targeted approaches that clin-ical outcomes will improve in this disease.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Received January 17, 2011; revised April 7, 2011; accepted April 18, 2011;published OnlineFirst May 16, 2011.

Rengan et al.





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2011;17:4192-4199. Published OnlineFirst May 16, 2011.Clin Cancer Res Ramesh Rengan, Amit M. Maity, James P. Stevenson, et al. DiseaseOutcomes in Chemoradiotherapy for Locally Advanced

Small Cell Lung Cancer: Improving−New Strategies in Non

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